Certain imidodithiocarbonates

ABSTRACT

This disclosure describes esters of dithioimidocarbonic acid having chemosterilant and larvicidal activity.

[ CERTAIN IMIDODITHIOCARBONATES [75] Inventors: William Wayne Brand, Hopewell;

Michael Stanley Schrider, South Bound Brook, both of NJ.

[73] Assignee: American Cyanamid Company,

Stamford, Conn.

[22] Filed: Oct. 28, 1973 [21] App]. No.: 410,842

[52] U.S. Cl 260/294.8 G; 260/294.8 E; 260/453 RW; 424/263; 424/301 51] Int. Cl. C07D 31/50; CO7C 119/00 [451 July 1, 1975 [58] Field 0fSearch...260/294.8 E, 294.8 6,453 RW [56] References Cited UNITED STATES PATENTS 3,832,351 8/1974 Tanaka et al. 260/2948 E Primary ExaminerAlan L. Rotman Attorney, Agent, or Firm-Edward A. Conroy, Jr.

[5 7] ABSTRACT This disclosure describes esters of dithiolmidoca rbonic acid having chemosterilant and larvicidal activity.

7 Claims, No Drawings CERTAIN IMIDODITHIOCARBONATES BRIEF SUMMARY OF THE INVENTION This invention relates to new organic compounds and, more particularly, is concerned with novel esters of dithioimidocarbonic acid and methods of preparing these compounds. the novel compounds of the present invention may be represented by the following general formula:

wherein R is chloro or methyl. R is chloro or methyl, and R and R are each selected from the group consisting of lower alkyl, lower alkylthiome'thyl, allyl, 2- chloroallyl, Z-methyl-allyl, propargyl, 4-pyridylmethyl and benzyl, with the proviso that R and R cannot both be lower alkyl. Suitable lower alkyl groups contemplated by the present invention are those having up to six carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-buty], isobutyl, 2-pentyl, 3-pentyl, 2-hexyl, isohexyl, etc. A preferred class of compounds within the above general formula are those wherein R is methyl and R is chloro.

This invention further relates to the use of these esters of dithioimidocarbonic acid in controlling acarina. More particularly, it relates to controlling acarina by suppressing the fecundity thereof with effective amounts of these compounds. Further, it relates to the control of acarina by applying the compounds to adult acarina, or to the habitat or dietary media (such as foliage or vegetation, manure and the like) of acarina in an amount sufficient to suppress the fecundity thereof. It also relates to controlling acarina by applying a larvicidally effective amount of these compounds to the larvae, larval habitat, or dietary media of the larvae of acarina.

This invention also relates to a method for controlling lxodidae by suppressing the fecundity thereof. It further relates to controlling Ixodidae by applying a larvicidally effective amount of these esters of dithioimidocarbonic acid to the larvae, larval habitat, or dietary media of the larvae of Ixodidae. Still more particularly, this invention relates to a method for controlling ixodid ticks by applying a fecundity-suppressing amount of these esters of dithioimidocarbonic acid to adult ixodid ticks, orto the habitat or dietary media of ixodid ticks.

This invention further relates to chemosterilant and larvicidal compositionscontaining these esters of dithioimidocarbonic acid.

DETAILED DESCRIPTION OF THE INVENTION The novel compounds of the present invention are preferably prepared by reacting an appropriate dithiocarbamate ester with an appropriate reactive halide in accordance with the following reaction scheme:

Base

' SolveA 1 R wherein R, R R fandR are as previously defined and Y represents a suitable leaving group such as a reactive halo group or alkyl or aryl sulfonate. The reaction is generally carried out in the presence of l a base such as an alkali metal hydroxide, carbonate or bicarbonate,

i a tertiary amine or other weak base and (2) an organic solvent such as methyl alcohol or dimethylformamide. This reaction is carried out at a relatively low temperature, for example between about -l 0C. and 50 C, and preferably at about 0C. to 25C. The reaction product is isolated by pouring the reaction mixture into water and' extracting 'the aqueous solution with a waterinsoluble solvent such as diethyl ether, chloroform. and the like. The product is recovered from the extract by evaporation of the excess solvent and purified by distillation, dry-column chromatography. or recrystallization depending on the particular product being pre-.

The dithiocarbamate salt can be prepared by reacting the appropriate amine with carbon disulfide and base, or it can be synthesized from the appropriately substituted isothiocyanate by reaction with an alkali'metal hydrosulfide-in a suitable solvent. Alternatively, the intermediate dithiocarbamate ester can be prepared by reaction of an appropriate isothiocyanate with an appropriate thiol.

The compounds of the present'in'vention can also be prepared from the corresponding isocyanide dichlorides by the method described by E. Kuhle in Angew. Chem. Internat. Edit., 8, 20 (1969).

Typical compounds of the present invention which may be prepared by the above methods are, for example, n-pentyl (ethylthio )methyl (2,4- dichlorophenyl)dithioimidocarbonate, benzyl (isopropylthio )methyl (2,4-dichlorophenyl )dithioimidocarbonate, 'allyl n-propylthio)methyl '(2,4- dichlorophenyl)dithioimidocarbonate, allyl 2-propynyl (2,4-dichlorophenyl )dithioimidocarbonate, 2-propynyl (sec-butylthio)methyl (2,4-xylyl)dithioimidocarbonate, 2-methylallyl ('n-butylthio)methyl (2,4-xylyl)dithioimidocarbonate, isopropyl benzyl (2,4-xylyl)dithioimidocarbonate, n-propyl' (amylthio)methyl (2- 3 chloro-p-tolyl )dithioimidocarbonate, isobutyl (nhexylthio )methyl (2-chloro-p-tolyl )dithioimidocarbonate, and sec-butyl 2-chloroallyl (2-chloro-ptolyl)dithioimidocarbonate.

The novel compounds of the present invention may be used to control infestations of acarina on mammals and birds, generally, and are particularly useful in controlling tick infestations of livestock, such as cattle, swine, sheep and goats, of domestic pets, such as dogs and cats, of rabbits, of poultry such as chickens, turkeys, geese, and the like, of fur bearing animals such as mink, foxes, chinchillas, and the like. When the compounds of this invention are utilized as control agents for acarina. such compounds may be brought into contact in effective amounts with the adult pest, ova or larva of said pests, or they may be applied to the habitat, breeding grounds and/or dietary media of said pest or larvae, that is, organic matter. living or dead which forms their food. The application is preferably made at a dosage concentration which is sublethal foradult acarina, but which level provides ultimate control of said acarina through ovicidal or larvicidal activity or by suppression of fecundity, inhibition of metamorphosis, juvenile hormone effect or chemosterilization of said pests. However. in some cases adult pests .may receive.

prepared by grindingtogether an inert solid diluent such as attapulgite, kaolin, walnut shell flour, diatomaceous earth, ground corn cob grits, or ground cocoanut shell, and the active ingredient, where such active ingredient is in solid form. Where the active ingredient is liquid, it may be sprayed on the carrier and thoroughly mixed with it or it may be dissolved in a solvent such as acetone or xylene, and the solution sprayed on the solid carrier. Dusts usually contain from about 1% to 15% by weight of active ingredient, whereas concentrates may contain from about 16 to about 85% by weight of the active material. Wettable powders are prepared in the same fashion as dust concentrates, excepting that about 5% to by weight ofa surfactant is also added.

The compounds of the present invention may alsobe prepared as emulsifiable concentrates by dissolving or dispersing about 10 to 75% by weight of the active compound in a suitable solvent or carrier such as a petroleum distillate having a minimum aromatic content of 85% and admixing therewith about l0 by weight of an emulsifier such as polyoxyethylene derivatives and blends with alkyl aryl sulfonates. These concentrates are also generally dispersed in water or other suitable solvent for application. Wettable powders and emulsifiable concentrates are particularly useful since they can be diluted with water and applied as dilute liquid sprays to an infested area or animal for which protection is sought or they may be sprayed on or applied topically to animal which are to be protected from attack. In the latter situation the dilute formulation may be used as dips as well as sprays. Field application of these formulations may be made by conventional equipment, such used to control lxodidae populations by application thereof to Argasid or lxodid adult female ticks as Boophilus, Amblyomma, Anocentor, Dermacentor, lxodes, Haemaphysalis, Hyalomma, Rhipicentor, Margarpus, Rhipicephalus, Argas, Otobius and Ornithodors whereby fecundity is suppressed, i.e., their egg production is inhibited, or if laid, the embryogenesis of the egg is prevented.

The dosage employed will depend upon the particular composition to be used, the particular kind or kinds of acarina to be controlled, the degree of infestation and the particular result desired. These factors are those ordinarily encountered in animal husbandry to control and/or prevent infestations of ectoparasites; these factors are well known to the practitioners of the art. In general larger doses are required to control an already existing infestation. In the Practice of this invention, we have found that the fecundity of acarina can be suppressed by thoroughly spraying an infested animal with a dilute aqueous. dispersion containing from'0.00l% active ingredient w/w to 0.2% active ingredient w/w; each animal is thoroughly sprayed with fromv 1.5 to l0 liters of solution. Control of the larval stages of acarina on animals can be obtained with the ester of dithioimidocarbonic acid in dilute formulations containing from about 0.00l% w/w to 0.20% w/w of. the active ingredient, preferably 0.00l% w/w to 0. IO% w/w of the .active ingredient. Control of infested areas can be effected by the application of from about /a pound to pounds of active ingredient per acre. Preferably, the rate of application ranges from about /8 pound to 10 pounds of active ingredient per acre.

The preparation and the effectiveness of the novel compounds of the present invention are further demonstrated in the following examples which are not to, be taken as being limitative of the present invention. Unless otherwise indicated all parts and percentages employed herein are by weight. 1

EXAMPLE 1 A solution of 52.4 g. (0.44 mole) of propargyl bromide in 400 mlyof methanol is cooled to 05C. with an ice bathL'To this is added portionwise during minutes, 63.9 g. (0.2 mole) of triethylammonium (4- chloro-o-tolyl)dithiocarbamate followed by the dropwise addition during 20 minutes of a solution of 28 ml. (0.2 mole) of triethylamine in ml. of methanol. Stirring is continued for 2 days during which the reaction mixture is warmed to room temperature. The reaction mixture is then filtered. and the solids are washed with methanol giving 9.6 g. (16.3% yield) of the product as a white solid. The filtrate is diluted to 3 liters with diethyl ether and the precipitated triethylamine hydrobromide (63.9 g.. 88%) is filtered off and washed with diethyl ether. The filtrate is then concentrated in vacuo, and the residual brown semisolid is stirred with 600 ml. of hot hexane, filtered hot to remove triethylamine hydrobromide, and allowed to cool. The resulting solid weighs 21.9 g. (37.3% yield), giving a total yield of 3L5 g. (53.6%) of product. Recrystallization from hexane-pentane gives white needles, mp 74.5-75.5C.

EXAMPLE 2 Preparation of diallyl (4-chloro-o-tolyl )dithioimidocarbonate To 18.3 g. (0.067 m.) of allyl (4-chloro-otolyl)dithiocarbamate and 2.74 g. (0.067 m.) of sodium hydroxide beads in 100 ml. of dimethylformamide is added 8.1 g. (0.067 m.) of allyl bromide, with occasional cooling to keep the temperature at C. After the beads are completely dissolved the mixture is poured into 800 ml. of water and extracted with 100 ml. of chloroform. The aqueous layer is extracted again with 100 ml. of chloroform. and the chloroform extracts are combined and washed with water. On drying and concentration, a yellow liquid is obtained which is passed through a drycolumn using 5% methylene chloride in hexane, and 9.8 g. (49% theory) of a pale yellow liquid is obtained. Nuclear magnetic resonance and infrared spectra are in agreement with the assigned structure.

EXAMPLE 3 Preparation of allyl (methylthio)methyl (2,4.-xylyl)dithioimidocarbonate Chloromethyl methyl sulfide is allowed to react with 1 allyl (2,4-xy1y1)dithiocarbamate following the proce dure' of Example 2. There resulted a 77% yield of yellow oil, the nuclear magnetic resonance and infrared spectra of which are consistent with the desired prod- UCt.

EXAMPLE 4 Preparation of ethyl 2-propynyl (4-ch1oro-o-tolyl)dithioimidocarbonate EXAMPLE 5 Preparation of allyl (methylthio)methyl (4-chloro-o-to1yl)-dithiomidocarbonate Allyl (4-chloro-o-toly1)dithiocarbamate is allowed to react with chloromethyl methyl sulfide following the procedure of Example 2. There results a 46.5% yield of product having nuclear magnetic resonance and infrared spectra, and elemental analysis in agreement with the assigned structure.

EXAMPLE 6 Preparation of allyl tert-butyl (4-chloro-o-to1yl )dithioimidocarbonate To 9.2 g. (0.05 m.) of (4-ch1oroo-toly1)isothiocyanate and 2.1 g. (0.05 m.) of sodium hydroxide beads in 50 ml. of dimethylformamide, is added 4.5 g. (0.05 m.) of t-butyl mercaptan. Occasional cooling is necessary to keep the temperature at 25C. After one hour, 6.1 g. (0.05 m.) of allyl bromide is added, dropwise, keeping the temperature at 25C. After an additional hour the solution is poured into 500 ml. of water and 100 ml. of chloroform and the chloroform layer is separated. The aqueous phase is extracted with another 100 ml. of chloroform, and the chloroform layers are combined and washed with water. On drying and concentration,

an orange liquid is obtained which is passed through a dry-column using 5% methylene chloride in hexane as the eluent to obtain 10.2 g. (64% of theory) of a pale yellow liquid. The infrared and nuclear magnetic resonance spectra are in agreement with the assigned structure.

EXAMPLE 7 Preparation of allyl ethyl (4-chloro-o-tolyl)dithioimidocarbonate Ethyl (4-chloro-o-tolyl)dithiocarbamate is allowed to react with allyl bromide following the procedure of Example 2. There results an 85.6% yield of a liquid, b.p. 132.5l 34.5C., 0.1 mm., having infrared and nuclear magnetic resonance spectra, and elemental analysis in agreement with the assigned structure.

EXAMPLE 8 Preparation of ethyl Z-methylallyl (4-ch1oro-o-tolyl)dithioimidocarbonate Ethyl (4-chloro-o-tolyl )dithiocarbamate is allowed to react with methallyl chloride following the procedure of Example 2. There results a 55% yieldof product hav ing infrared and nuclear magnetic resonance spectra in agreement with the assigned structure. I

EXAMPLE 9 Preparation of bis(2-chloroa1lyl) (4-chloro-o-tolyl )dithioimidocarbonate To a stirred mixture of 16.0 g. (0.05 mole) of triethylammonium (4-chloro-o-tolyl)dithiocarbamate. 5.0 g. (0.05 mole) Oftriethylamine, and ml. of dimethylformamide is added dropwise l 1.1 g. (0.1 mole) of 2,3- dichloro-l-propene. The resulting mixture is stirred for several hours, poured into water, and extracted with ether. The ether extract is washed with water, dried and concentrated. The residue ispurified on a silica gel dry column with 5% methylene chloride in hexane as eluent, giving 7.1 g. (38.5% yield) ofa pale yellow liquid. Infrared and nueclear magnetic resonance spectra are in agreement with the assigned structure;

EXAMPLE 10 Preparation of allyl 2-propyny1 (4-chloro-o-tolyl )dithioimidocarbonate Propargyl bromide was allowed to react with allyl (4- chloro-o-tolyl)dithiocarbamate following the procedure of Example 2. There resulted a 14% yield of the product after purification.

EXAMPLE 1 1 Preparation of di-2-propynyl (2,4-xylyl )dithioimidocarbonate A solution of 13.1 g. (0.1 1 mole) of propargyl bromide in ml. of methanol is cooled to 05C. with an ice bath. To this is added portionwise 14.9 g. (0.05 mole) of triethylammonium (2,4-xylyl)dithiocarbamate. The reaction mixture is stirred at 0-5C. for 15 minutes after which a solution of 7 ml. (0.05 mole) of triethylamine in 10 ml. of methanol is added dropwise. After 30 minutes, the ice bath is removed, and the reaction mixture is stirred overnight. The reaction mixture is then concentrated, and the residue is partitioned between water and diethyl ether. The ether solution is washed with water, 6M HCl, water, and finally saturated NaHCO;,. The other solution is then dried and the solvent distilled out leaving ll.3l g. of a yellow oil.

The fraction containing product is taken'up in diethyl ether, treated with charcoal and anhydrous magnesium sulfate. filtered, and concentrated giving 0.5 g. (3.7% yield) of a brown-yellow solid, mp. 38-42C., having infrared and nuclear magnetic resonance spectra consistent with the desired product.

EXAMPLE 12 Preparation of allyl hexyl I (4-chloro-o-tolyl)dithioimidocarbonate distillate is then purified on a dry column of silica gel with a mixture of methylene dichloride 95% hexane to separatean isothiocyanate impurity. A yellow band is then eluted from the column and concentrated to obtain 9.8 g. of a pale yellow liquid which has a nuclear magnetic resonance spectrum in agreement with the assigned structure.

EXAMPLE 13 Preparation of ethyl 4-pyridylmethyl (4-chloro-o-tolyl )dithioimidocarbonate To 164g. of ethyl (4-chloro-o-tolyl)dithiocarbamate and 9i84 g'jof 4 -picolyl chloride hydrochloride in 100 ml. of'dirnet'h'ylformamide is added 12.2 g. of triethyl amine, dropwise, while .keeping the temperature at C. The reaction mixture is then s'tirred at room temperature for about one hour, poured into water and ex tracted with two 250-ml. portions of chloroform. The combined chloroform extract is washed with water, dried and concentrated to a dark reddish liquid. The liquid is purified on a dry column of silica gel with a mixture of 66;6% methylene dichloride 33.3% methyl ethyl ketone. The separation of the various fractions is determined by the presence of ultraviolet absorption. A major fraction preceding a yellow band is concentrated to obtain 7.4 g. of a yellow-orange liquid which has infrared and nuclear magnetic resonance spectra which corresponded to the assigned structure.

EXAMPLE 14 Preparation of dibenzyl (4-chloro-o-tolyl )dithioimidocarbonate tracted with 2 X 250 ml. of chloroform. The chloro-' form extract is washed with one liter of water, dried and concentrated to obtain 23.4 g. of a yellow-orange liquid. This material is purified on a dry column of Si] ica gel using a solution of l()% methylene dichloride hexane. A fraction immediately following a bright yellow band is separated'and concentrated to obtain 5.0 g. of-a white solid mp. 8486C. Y

EXAMPLE 15 Preparation of bis(2-c hloroallyl) (2,4-dichlorophenyl)dithioimidocarbonate The procedure of Example 9 is used except that triet- 'hylarn monium-('2,4 dichlorophenyl)dithiocarbamate is used instead of triethylammoni'u'm-(4-chloro-o-tolyl) dithiocarbamate. The product obtained has infrared and nuclear magnetic resonance spectra in agreement with the assigned structure. I v I EXAMPLE'l6 Preparationof benz'yl ethyl (4-chloro-o-tolyl )dithioir'riidocarbonate To 7.37 grams (0.03 mole) of ethyl (4-chloro-otolylldithiocarbamate in 75 mlf of t-butanol at 20C. is added,.gradually. 3.36 grams (0.03 mole) of potassium t-butoxide. To this .mixture is. gradually added 5.13 grams (0.03 mole) of benzyl bromide ,while allowing the temperature to rise to about 31C. The mixture is stirred atro om temperature forabout 2.5 hours, filtered and the filter cake is washed with diethyl. ether. The filtrate is filtered asecond time and evaporated to dryness to obtain an oil. The oil is diluted with ml. of pentane and allowed to stand overnight. The diluted solution is filtered and the filtrate is evaporated to dryness to obtain 9.88 grams of a viscous oil. The viscous oil is distilled in vacuo toobtain afraction boiling between 173C. to l76C. at 0.025 Torr.

EXAMPLE 17 Preparation of ethyl (methylt hio)methyl 4- chl oro-o-to l'ylj-dithioimidocarbonate To 7.37 grams (0.03 mole) of ethyl. (4-chloro-otolyl)dithiocarbamate in 75 ml. of t-butanol is added 3.36 grams (0.03 mole) of potassium t-butoxide and then 3.0.grams:(0.031 mole) of chloromethyl methyl thioethenUpon completion of addition of the latter, the mixture is stirred at room temperature for- 3.5 hours. 75 ml. of pentane is added thereto, and the reaction mixture is filtered. The filter cake is washed with pentane, and the combined filtrate and washings are concentrated in vacuo to obtain. an ambencolored oil. Distillation of the oil in vacuo gives a pale yellow oil boiling at l44C.-to 148C. at 0.04 mm to 0.05 mm. pressure. i

EXAMPLE 18 Preparation of di-2-propynyl (2-chlo'ro-p-toly l )dithioimidocarbonate Propargyl bromide is allowed to react with- 2-' propynyl (2-chloro-p-tolyl)dithiocarbamate following theprocedure of Example 2. Theiresulting product is in agreement with the assigned structure.

EXAMPLES 36 Suppression of Fecundity. and Chemosterilant Effect in lxodidae The efficacy of the compounds of the present invention for suppression of fecundity in ticks is demonstrated in the following tests wherein engorgedadult female Boophilus microplus ticks which have dropped from cattle are collected and used for testing.

The compound to be tested is dissolved in a 35% acetone/65% water mixture in sufficierit amount to provide 500 ppm., 1,000 ppm. and 2,000 ppm. of compound in the test solution: Ten ticks per treatment are used and they are immersed in test solution for three to five minutes, then removed and placed in dishes and held in incubators for two to three weeks 289C. Counts of ticks layingeggs are then made and recorded. Eggs which were laid are placed in containers and kept for one month to observe hatching and to determine chemosterilant effect. For each test. ten nonresistant ticks as well as ten ethion-resistant and ten dioxathiom resistant'ticks are used'since thelatter two are among the most difficult of their kind to control. Results of these tests are given-in Tables I and II belowi The rating system used for each tick is as follows:

Rating' System v I Result Score No oviposition "4 Partial oviposition. no hatch 3. Total oviposition. no hatch 2 Partial oviposition, viable eggs 1 Normal oviposition and hatch 0 TABLE I Chemosterilant Efficacy of Dithioimidocarbonates Chemosterilant Efficacy of Ditiiioiinidb carbonates EXAMPLES 37-50 Larvicidal Activity The effective control of acarina larvae is demonstrated in the following tests with larvae of Boophilus nzicroplus, a one-host tick which remains on a single host through its three life stages, i.e., larva, nymph and adult. In these tests. a 10% acetone/% water mixture contains from 1.0 to ppm. of test compound. Twenty larvae are enclosed in a pipet sealed at one end with a gauze material and solution containing the test compound is then drawn through the pipet with a vacuum hose simulating a spray system. The wet ticks are then held for 48 hours at room temperature and 80% relative humidity and mortality is determined. The rating system used is as follows:

Rating System The results of these test are given in Table Ill and IV below. 

1. DIPROPARGYL (4-CHLORO-O-TOLYL)DITHIOIMIDO-CARBONATE.
 2. Allyl (methylthio)methyl (4-chloro-o-tolyl)-dithioimidocarbonate.
 3. Ethyl (methylthio)methyl (4-chloro-o-tolyl)-dithioimidocarbonate.
 4. Ethyl 4-pyridylmethyl (4-chloro-o-tolyl)di-thioimidocarbonate.
 5. Dipropargyl (2,4-xylyl)dithioimidocarbonate.
 6. Allyl (methylthio)methyl (2,4-xylyl)dithioimidocarbonate.
 7. Di(2-chloroallyl) (2,4-dichlorophenyl)dithioimidocarbonate. 